Ghada El-Hajj Fuleihan

IOF position statement: vitamin D recommendations for older adults

This position paper of the International Osteoporosis Foundation makes recommendations for vitamin D nutrition in elderly men and women from an evidence-based perspective.

Alendronate Prevents Postmenopausal Bone Loss in Women without Osteoporosis: A Double-Blind, Randomized, Controlled Trial

Osteoporosis is characterized by low bone mass and architectural changes in bone that render the skeleton brittle and susceptible to fracture [1]. As the elderly population grows, the worldwide annual incidence of hip fractures is projected to increase from 1.7 million in 1990 to 6.3 million by 2050, placing great economic strain on health care systems [2]. Currently, a 50-year-old woman is estimated to have a risk as high as 40% for sustaining a fracture related to osteoporosis at some point in the future [3]. The age-adjusted risk for fracture seems to be increasing, and this risk may be an underestimate for the future [4]. Bone loss after menopause, which results in low bone density, is an important determinant of risk for fracture, although other factors (such as advanced age, hip geometry, and falls and injuries) also contribute [5, 6]. Bone loss is most rapid during the first few years after menopause, but evidence suggests that the rate of loss also becomes accelerated in advanced old age [7, 8]. One strategy to reduce the number of fractures in postmenopausal women is to begin treatment for osteoporosis only in patients who are at high risk for fracture, including those with osteoporosis or previous fragility fractures. Pharmacologic therapy in women with osteoporosis with or without fractures reduces the incidence of fracture by about 50% [9, 10]. However, half of women who would have sustained fractures without treatment still do so with treatment. Thus, preventing rather than treating osteoporosis is a more appealing clinical objective because it can avoid the increased risk for fracture. There may also be an advantage in terms of preserving the normal microarchitecture of bone. Preventing bone loss associated with menopause and aging and maintaining normal microarchitecture provide important opportunities for the prevention of osteoporosis and fractures. Estrogen is effective in preventing bone loss in early and late postmenopausal women, but it must be taken over the long term to decrease the incidence of vertebral and hip fractures [11]. Estrogen also relieves menopausal symptoms and, in epidemiologic cohort studies, seemed to protect against cardiovascular disease. However, most women who begin estrogen therapy do not continue it for more than a year, in part because of such side effects as breast tenderness, headache, fluid retention, and withdrawal bleeding [12, 13]. Although the benefits of estrogen therapy outweigh the risks in most women, concern about risk for breast cancer is sufficiently great that many women avoid estrogen therapy [14, 15]. Alendronate sodium (monosodium 4-amino, 1-hydroxybutylidene-1, 1-bisphosphonate) is a potent and selective inhibitor of osteoclast-mediated bone resorption. Studies in animals with low bone mineral density have shown that alendronate therapy is associated with increased bone mass of normal quality and increased bone strength [16]. Alendronate treatment of osteoporosis in postmenopausal women induces progressive increases in bone density and a reduction in the incidence of new fractures of the vertebrae, hip, and forearm in osteoporotic women [9, 10]. We performed a 3-year randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy of alendronate therapy in preventing bone loss in healthy women who had recently experienced menopause. Methods Study Participants Healthy women aged 40 to 59 years who had experienced menopause 6 to 36 months before enrollment were eligible to participate in this study. Women were excluded if their spine bone mineral density was more than 2 SDs above or below normal peak bone mineral density or if they had a history of nontraumatic spine or hip fracture. Women with disorders of bone and mineral metabolism were also excluded, as were those with recent (within 1 year of study entry) major upper gastrointestinal diseases (such as peptic ulcer, esophageal disease, and malabsorption). Other exclusion criteria were previous treatment with bisphosphonates or fluoride (>1 mg/d) or treatment within the 12 months before enrollment with estrogen, progestin, calcitonin, glucocorticoids, anticonvulsant agents, phosphate-binding antacids, or excessive vitamin A or vitamin D. Women who regularly used (>four times per week) any medication that had the potential to cause gastrointestinal irritation (such as aspirin), who smoked more than 20 cigarettes per day, or who drank three or more alcoholic beverages per day were also excluded. Four hundred forty-seven women met the inclusion criteria and were enrolled at 15 centers throughout the world. The target sample size of 250 women completing the study was selected to detect a difference in bone density of 2.4% between an individual alendronate dosage and placebo at a P value of 0.05 or less, with 95% power using an SD of 3.3% that was obtained from 1-year bone density data in placebo recipients [17]. All centers conducted the study with appropriate approval from the institutional review boards, and all participants gave informed consent. Treatment Participants were randomly assigned (in allocation blocks of five) to one of five regimens: placebo for 3 years; alendronate at 1, 5, or 10 mg/d for 3 years; or alendronate at 20 mg/d for 2 years followed by placebo for 1 year (20/0 mg/d). In all groups, double-blinding was maintained for all 3 years. Alendronate and placebo tablets were identical in size, shape, and color. The women were instructed to take the study drug daily at least 1 hour before breakfast or, as a less desirable alternative, at least 2 hours after a meal and 1 hour before the next meal. All participants also received a daily supplement of calcium carbonate (Os-Cal 500, Smith-Kline Beecham Consumer Brands, LP, Pittsburgh, Pennsylvania, or the equivalent) unless dietary calcium intake exceeded 1000 mg/d. This supplement was usually taken with the evening meal. After beginning therapy, each participant was seen at months 1 and 3 and every 3 months thereafter. Eight participants (four in the placebo group and four in the 1-mg/d group) lost more than 6% of their spine bone density at 24 months relative to their baseline measurements and were therefore designated fast bone losers. Seven of these participants completed the study; from month 24 to the end of the study, they received 5 mg of open-label alendronate per day. The other patient discontinued therapy at month 24. Bone Mineral Density Bone mineral density of the spine, proximal femur, total body, and forearm was measured every 6 months by dual-energy x-ray absorptiometry with a Hologic QDR-1000, 1000/W, or 2000 densitometer (Waltham, Massachusetts) or a Lunar DPX-L densitometer (Madison, Wisconsin). One bone density quality assurance center (Oregon Osteoporosis Center) that remained blinded to treatment allocation was responsible for the quality control of all participant and phantom calibration scans [18]. Factors to correct for machine calibration drift were applied as necessary. The primary end point was bone mineral density of the lumbar spine; the other most important end points were bone mineral density of the femoral neck, trochanter, and total body. Bone mineral density of the total body, total hip, and forearm was measured at the centers that had densitometers capable of performing these measurements (11 centers measured bone mineral density of the total body; 10 centers measured bone mineral density of the total hip and forearm). Biochemical Markers and Indices of Mineral Metabolism Fasting serum and urine samples (second morning void) were obtained at all clinic visits except those in months 27 and 33. The resorption markers included urine deoxypyridinoline, measured by high-pressure liquid chromatography, and (in a subgroup of 268 participants) urine N-telopeptide cross-links of type I collagen (Ostex, Seattle, Washington). Each of these markers was expressed as a ratio to urine creatinine. Serum osteocalcin levels, measured by radioimmunoassay (INCSTAR, Stillwater, Nebraska), and serum bone-specific alkaline phosphatase levels were used to assess the rate of bone formation. Levels of serum calcium, phosphorus, intact parathyroid hormone (measured by immunoradiometric assay), and 1,25 dihydroxyvitamin D (measured by competitive binding assay) were also determined to assess the effects of treatment on mineral metabolism. N-telopeptide levels were measured by Medical Research Laboratories (Highland Heights, Kentucky). All other assays were done at Corning-Nichols Institute (San Juan Capistrano, California). Safety Evaluations At each visit, vital signs were measured and any new or worsening symptoms were recorded. Physical examinations were performed at the baseline, month 3, and yearly visits. Standard laboratory safety evaluations (including evaluations of hematologic, renal, and liver function) were performed at every visit. Investigators reported any unfavorable or unintended clinical or laboratory events as adverse experiences. After 3 years of therapy, biopsy specimens of transiliac bone were obtained for histologic and histomorphometric assessment from 55 women who provided specific informed consent for this procedure. These analyses were performed, as previously described, by a single investigator who was blinded to treatment groups [19]. Statistical Analysis The Tukey trend test [20] was used to assess the trend in response with increasing alendronate dosages. The 20/0-mg/d group was excluded from this test because of the change in dosage. This test uses the minimum P value, adjusted for multiplicity [21], that was obtained from tests of the regression sloped on three dosage scalings. The test is done in a stepwise manner, with the highest dosage eliminated, until the minimum P value exceeds 0.05. Dose-response relations were examined for the responses of the percentage change in bone density variables, natural logarithm (fraction of the baseline value) for biochemical variabl

Hypovitaminosis D in developing countries—prevalence, risk factors and outcomes

Hypovitaminosis D is a prevalent disorder in developing countries. Clinical manifestations of hypovitaminosis D include musculoskeletal disorders, such as nonspecific muscle pain, poor muscle strength and low BMD, as well as nonmusculoskeletal disorders, such as an increased risk of respiratory infections, diabetes mellitus and possibly cardiovascular diseases. In developing countries, the prevalence of hypovitaminosis D varies widely by and within regions; prevalence ranges between 30–90%, according to the cut-off value used within specific regions, and is independent of latitude. A high prevalence of the disorder exists in China and Mongolia, especially in children, of whom up to 50% are reported to have serum 25-hydroxyvitamin D levels <12.5 nmol/l. Despite ample sunshine throughout the year, one-third to one-half of individuals living in Sub-Saharan Africa and the Middle East have serum 25-hydroxyvitamin D levels <25 nmol/l, according to studies published in the past decade. Hypovitaminosis D is also prevalent in children and the elderly living in Latin America. Risk factors for hypovitaminosis D in developing countries are similar to those reported in Western countries and include extremes of age, female sex, winter season, dark skin pigmentation, malnutrition, lack of sun exposure, a covered clothing style and obesity. Clinical trials to assess the effect of vitamin D supplementation on classical and nonclassical clinical outcomes in developing countries are needed.

Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations.

Short- and Long-Term Safety of Weekly High-Dose Vitamin D3 Supplementation in School Children

BACKGROUND Hypovitaminosis D is prevalent in youth worldwide, but the safety of vitamin D at doses exceeding 200 IU/d is unknown in this age group. We assessed the safety of high doses of vitamin D(3) administered to apparently healthy schoolchildren. METHODS To assess short-term safety, 25 subjects randomly received placebo or vitamin D(3) at doses of 14,000 IU/wk for 8 wk. To assess long-term safety, 340 subjects randomly received placebo, vitamin D(3) as 1,400 IU/wk or 14,000 IU/wk for 1 yr. Biochemical variables were monitored at 0, 2, 4, 6, and 8 wk and 8 wk off therapy in the short-term study and at 0, 6, and 12 months in the long-term study. RESULTS In both the short- and long-term studies, mean serum calcium and 1,25-hydroxyvitamin levels did not change in any group. In the short-term study, mean 25-hydroxyvitamin concentrations increased from 44 (+/- 11) to 54 (+/- 19) ng/ml in the treated groups (P = 0.033). In the long-term study, mean 25-hydroxyvitamin D levels increased from 15 +/- 8 to 19 +/- 7 ng/ml (P < 0.0001) in subjects receiving 1,400 IU/wk and from 15 +/- 7 to 36 +/- 22 ng/ml (P < 0.0001) in the group receiving 14,000 IU/wk. No subject developed vitamin D intoxication. CONCLUSION Vitamin D(3) at doses equivalent to 2000 IU/d for 1 yr is safe in adolescents and results in desirable vitamin D levels.

Official Positions for FRAX ® Clinical Regarding International Differences. From Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX ®

Osteoporosis is a serious worldwide epidemic. Increased risk of fractures is the hallmark of the disease and is associated with increased morbidity, mortality and economic burden. FRAX® is a web-based tool developed by the Sheffield WHO Collaborating Center team, that integrates clinical risk factors, femoral neck BMD, country specific mortality and fracture data and calculates the 10 year fracture probability in order to help health care professionals identify patients who need treatment. However, only 31 countries have a FRAX® calculator at the time paper was accepted for publication. In the absence of a FRAX® model for a particular country, it has been suggested to use a surrogate country for which the epidemiology of osteoporosis most closely approximates the index country. More specific recommendations for clinicians in these countries are not available. In North America, concerns have also been raised regarding the assumptions used to construct the US ethnic specific FRAX® calculators with respect to the correction factors applied to derive fracture probabilities in Blacks, Asians and Hispanics in comparison to Whites. In addition, questions were raised about calculating fracture risk in other ethnic groups e.g., Native Americans and First Canadians. In order to provide additional guidance to clinicians, a FRAX® International Task Force was formed to address specific questions raised by physicians in countries without FRAX® calculators and seeking to integrate FRAX® into their clinical practice. The main questions that the task force tried to answer were the following: The Task Force members conducted appropriate literature reviews and developed preliminary statements that were discussed and graded by a panel of experts at the ISCD-IOF joint conference. The statements approved by the panel of experts are discussed in the current paper.

Hypovitaminosis D in a Sunny Country

To the Editor: Some normal subjects and a substantial proportion of patients with various illnesses in the United States and northern Europe have vitamin D insufficiency,1–4 but information from co...

Predictors of bone density in ambulatory patients on antiepileptic drugs

BACKGROUND AND AIM Antiepileptic drugs are associated with bone loss and fractures. Data in children is scarce and the impact of new therapies and of low vitamin D is not clear. This study assessed predictors of bone mineral density (BMD) in 225 ambulatory patients with epilepsy. METHODS BMD and detailed clinical information were obtained from 137 adults mean age of 31 years, on therapy for a mean of 11.7 years, and 88 children mean age of 13 years, on therapy for an average of 4.7 years. RESULTS Hypovitaminosis D was common in epileptic patients. BMD was reduced in adults but not children with epilepsy, by 0.3-0.6 SD depending on the skeletal site measured, compared to controls. Duration of treatment, but not vitamin D levels, was negatively correlated with BMD at the hip in adults. Bone density was reduced with the use of both enzyme and non-enzyme-inducing drugs, with both mono- and polytherapy, and was most severely reduced at the spine and hip with the use of enzyme-inducing drugs. In the multivariate analyses, polytherapy in children and duration of therapy and enzyme-inducing drugs in adults were independent predictors of BMD. CONCLUSION Antiepileptic drug therapy is associated with low bone density at clinically relevant skeletal sites, projecting into a possible doubling of fracture risk. Age, therapy duration, polypharmacy and the use of enzyme-inducing drugs were risk factors. Newer drugs may be associated with deleterious effects on bone. Skeletal monitoring with varying intervals, depending on the individual risk profile, is indicated.

Hypovitaminosis D in the Middle East and North Africa: Prevalence, risk factors and impact on outcomes

Background: The Middle East and North Africa (MENA) region registers some of the highest rates of hypovitaminosis D worldwide. Aim: We systematically reviewed the prevalence of hypovitaminosis D, rickets and osteomalacia, their predictors and impact on major outcomes, in the region. Methods: Medline, Pubmed and Embase search engines, entering keywords and concepts, combined with individual countries of interest, were used. Search was limited years 2000–2012; and review articles were used for the period preceding year 2000. Results: Rickets and osteomalacia still occur in this sunny region. Hypovitaminosis D prevails, with rates varying 30–90%, considering a desirable serum 25 hydroxy-vitamin D [25(OH)D] of 20 ng/ml. Advancing age, female gender, multi-parity, clothing style, season, socio-economic status and urban living are recognized predictors of hypovitaminosis D in adults. Prolonged breastfeeding without vitamin D supplementation and low dietary calcium intake are the recognized risk factors for rickets and hypovitaminosis D in children.. Associations with pain score and disease activity in rheumatologic disorders, viral load and interleukins in hepatitis C, BMI, lipids and insulin sensitivity, blood pressure, heart failure and mortality are described. Sun exposure in adults decreased prevalence of metabolic syndrome in one study. Few randomized vitamin D trials revealed that the majority of mothers or children failed to achieve a desirable 25(OH)D level, even with doses by far exceeding current recommendations. A trial in adolescent girls reveals substantial bone and lean mass increments. Conclusion: Hypovitaminosis D is prevalent in MENA. The lack of populations based studies, gaps in studies in infants, pre-pubertal children and pregnant women, hinder the development of region specific guidelines and constitute a major obstacle to impact this chronic and most often subclinical disease.

Serum 25-Hydroxyvitamin D Levels: Variability, Knowledge Gaps, and the Concept of a Desirable Range.

Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25‐hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40 ng/mL (50 to 100 nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20 ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60 ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at‐risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600 IU for children and 800 IU for adults. A total daily allowance of vitamin D of up to 1000 IU in the pediatric age groups, and up to 2000 IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non‐white populations.